Solution NMR Structure of a Ligand/Hybrid-2-G-Quadruplex Complex Reveals Rearrangements that Affect Ligand Binding

Angewandte Chemie
Julia Wirmer-BartoschekHarald Schwalbe

Abstract

Telomeric G-quadruplexes have recently emerged as drug targets in cancer research. Herein, we present the first NMR structure of a telomeric DNA G-quadruplex that adopts the biologically relevant hybrid-2 conformation in a ligand-bound state. We solved the complex with a metalorganic gold(III) ligand that stabilizes G-quadruplexes. Analysis of the free and bound structures reveals structural changes in the capping region of the G-quadruplex. The ligand is sandwiched between one terminal G-tetrad and a flanking nucleotide. This complex structure involves a major structural rearrangement compared to the free G-quadruplex structure as observed for other G-quadruplexes in different conformations, invalidating simple docking approaches to ligand-G-quadruplex structure determination.

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Citations

Dec 12, 2017·Chembiochem : a European Journal of Chemical Biology·Andrea FunkeKlaus Weisz
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Jul 19, 2019·Angewandte Chemie·Thi Hong Anh TruongAnh Tuân Phan
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Jan 7, 2022·Journal of the American Chemical Society·Susanta HaldarShozeb Haider

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